tbuckley/cabot-search huggingface dataset:
Abstract 5533: YIV-906 could modulate nuclear factor of activated T-cells (NFAT) activity of T cells for immune checkpoint blockade therapy and CAR T-cell therapy
Authors: Wing Lam, Shwu-Huey Liu, Peikwen Cheng, Yung-Chi Cheng
Journal: Cancer Research (2022)

Abstract YIV-906 is a standardized botanical drug inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea, and vomiting. Results from seven Phase I/II to II clinical studies suggest that YIV-906 has potential to prolong survival and improve quality of life for patients who have liver, pancreatic, colorectal, and rectal cancer and received chemotherapy and/or radiation therapy. Currently, a phase II international clinical trial for using YIV-906 plus sorafenib to target HBV positive hepatocellular carcinoma as first line therapy (NCT04000737) had been initialized. Recently, we demonstrated that YIV-906 could enhance anti-tumor activity of anti-PD1 against hepatoma in mice by enhancing both adaptive immunity and innate immunity thought promoting T cell activation by modulating IDO activity and potentiating IFNg action to polarize macrophages into M1-like type. Here, by using Jurkat cells-staphylococcal superantigen E (SEE)-Raji cells cell culture model, we demonstrated that YIV-906 could promote T cell activation with up-regulation of CD69 by modulating nuclear factor of activated T-cells (NFAT) activity. This could be due to that YIV-906 could trigger protein phosphorylation of T cell receptor signaling cascades including, Lck, Fyn, Zap70, LAT and Pyk2. Importantly, YIV-906 could enhance Anti-PD1 action to recuse the depressed NFAT activity of Jurkat cells-PD1 cells when incubated with Raji-PD-L1 cells. In addition, YIV-906 could also enhance NFAT activity triggered by the interaction of chimeric antigen receptor (CAR-CD19-CD3z) on Jurkat cells and CD19 on Raji cells. Component S (Scutellaria baicalensis Georgi) of YIV-906 was found to play key roles of the above activities. Flavonoids of S, such as baicalein, chrysin and oroxylin A, were identified to have modulation effect on NFAT activity. In conclusion, YIV-906 could modulate both adaptive immunity and innate immunity to facilitate immune checkpoint blockade therapy or CAR T-cell therapy for treatment of cancer in patients. This is worthy of further investigation. (Supported by research fund from Yiviva, inc) Citation Format: Wing Lam, Shwu-Huey Liu, Peikwen Cheng, Yung-Chi Cheng. YIV-906 could modulate nuclear factor of activated T-cells (NFAT) activity of T cells for immune checkpoint blockade therapy and CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5533.
Abstract 335: c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning
Authors: Caleigh Howard, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Sara LeMar, Paul Amador, Amit K. Chaudhary, Joseph D. Dekker, Jay Zhao, Ross Durland, Aimee Iberg
Journal: Cancer Research (2022)

Abstract Engineered toxin bodies (ETBs) are next-generation immunotoxins that harbor an antibody-derived targeting domain and a cytotoxic payload derived from Shiga-like toxin-1 catalytic subunit A (SLTA). SLTA has been engineered to reduce innate immunogenicity and therefore increase the safety of ETBs whilst retaining potent cytotoxic properties. When targeted via a binding domain, SLTA is internalized and routes to the cytosol leading to irreversible ribosome inactivation and ultimately cell death. ETBs have been developed to treat a wide variety of cancers, including breast, lymphoma, multiple myeloma and PD-L1 positive solid tumors. This technology holds promise for non-oncology indications as well, particularly as a targeted and non-genotoxic conditioning regimen for hematopoietic stem cell (HSC) ablation to prepare patients for autologous stem cell transplant. c-KIT (CD117) is a well-known marker of hematopoietic stem and progenitor cells and is overexpressed in a high percentage of certain cancers including GIST, SCLC and AML. While tyrosine kinase inhibitors such as imatinib are effective therapies for c-KIT mutant GIST, resistance often occurs by the development of secondary mutations in the intracellular signaling domains. Thus, c-KIT represents a potential ETB target for both oncological and HSC transplant conditioning indications. Here we present data highlighting the in vitro potency and efficacy of CD117-targeting ETBs on cancer cell lines as well as on primary human CD34+ HSCs. CD117-targeted ETBs demonstrate exquisite specificity in vitro by killing only target positive CD34+ cells at picomolar potency while sparing the progenitors that lack CD117 expression. However, relatively low CD117 receptor levels on CD34+ HSCs prevent complete killing in vitro, limiting the observed efficacy. To overcome this challenge, an additional cytotoxic payload was conjugated to the ETB molecule to capitalize on ETBs’ unique internalization and routing properties to deliver a secondary mechanism of action. ETB-drug conjugates (ETB-DCs) exhibited improved cytotoxicity in vitro, especially in CD117-low target cells. Moving forward, we plan to explore both the ETB and the ETB-DC therapeutic index in vivo with a series of CD117+ tumor efficacy and HSC depletion models. Citation Format: Caleigh Howard, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Sara LeMar, Paul Amador, Amit K. Chaudhary, Joseph D. Dekker, Jay Zhao, Ross Durland, Aimee Iberg. c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 335.
Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms
Authors: Eline J.M. Bertrums, Axel K.M. Rosendahl Huber, Jurrian K. de Kanter, Arianne M. Brandsma, Anaïs J.C.N. van Leeuwen, Mark Verheul, Marry M. van den Heuvel-Eibrink, Rurika Oka, Markus J. van Roosmalen, Hester A. de Groot-Kruseman, C. Michel Zwaan, Bianca F. Goemans, Ruben van Boxtel
Journal: Cancer Discovery (2022)

Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure. Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging. This article is highlighted in the In This Issue feature, p. 1825.
COVID-19 and liver disease
Authors: Jean-François Dufour, Thomas Marjot, Chiara Becchetti, Herbert Tilg
Journal: Gut (2022)

Knowledge on SARS-CoV-2 infection and its resultant COVID-19 in liver diseases has rapidly increased during the pandemic. Hereby, we review COVID-19 liver manifestations and pathophysiological aspects related to SARS-CoV-2 infection in patients without liver disease as well as the impact of COVID-19 in patients with chronic liver disease (CLD), particularly cirrhosis and liver transplantation (LT). SARS-CoV-2 infection has been associated with overt proinflammatory cytokine profile, which probably contributes substantially to the observed early and late liver abnormalities. CLD, particularly decompensated cirrhosis, should be regarded as a risk factor for severe COVID-19 and death. LT was impacted during the pandemic, mainly due to concerns regarding donation and infection in recipients. However, LT did not represent a risk factor per se of worse outcome. Even though scarce, data regarding COVID-19 specific therapy in special populations such as LT recipients seem promising. COVID-19 vaccine-induced immunity seems impaired in CLD and LT recipients, advocating for a revised schedule of vaccine administration in this population.
Abstract LB559: The X-linked gene for the helicase DDX3X is required for lymphoid differentiation and MYC-driven lymphomagenesis
Authors: Marion Lacroix, Hugues Beauchemin, Julie Ross, Jennifer Fraszczak, Peiman Shooshtarizadeh, Riyan Chen, Tarik Moroy
Journal: Cancer Research (2022)

Abstract The X-linked gene DDX3X encodes an RNA helicase and is mutated at high frequencies in several types of human B-cell lymphoma. Females have two active DDX3X alleles and males carry a DDX3Y homolog on the Y chromosome. We show here that pan-hematopoietic, homozygous deletion of Ddx3x in female mice perturbs erythropoiesis causing early developmental arrest. However, both hemizygous male and heterozygous female embryos develop normally, suggesting that one Ddx3x allele is sufficient for fetal hematopoietic development in females and that the Ddx3y allele can compensate for the loss of Ddx3x in males. In adult mice, loss of DDX3X affects hematopoietic progenitors, early lymphoid development, marginal zone, and germinal center B-cells as well as lymphomagenesis driven by an Eμ-Myc or λ-Myc transgene in a sex-dependent manner. A B-cell-specific depletion of both Ddx3x alleles induces a delay in tumorigenesis in female mice while Ddx3x deletion in male mice does not impact tumorigenesis. However, male Eμ-Myc mice lacking Ddx3x on a pan-hematopoietic way remained for the majority lymphoma-free. The few tumors that appeared in these male mice showed upregulated expression of DDX3Y indicating a requirement of DDX3 activity for lymphomagenesis. Our data reveal sex-specific roles of DDX3X in erythro- and lymphopoiesis as well as in MYC-driven lymphomagenesis, which are important when considering inhibition of DDX3 as a treatment of Myc dependent B-cell lymphoma. Citation Format: Marion Lacroix, Hugues Beauchemin, Julie Ross, Jennifer Fraszczak, Peiman Shooshtarizadeh, Riyan Chen, Tarik Moroy. The X-linked gene for the helicase DDX3X is required for lymphoid differentiation and MYC-driven lymphomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB559.
Abstract 10: Development of single cell spheroid as a tool to capture functional heterogeneity in head and neck cancer
Authors: Jyoti Pandey, Ritis Shyanti, Sanjay V. Malhotra, Rupesh Chaturvedi, Rana P. Singh
Journal: Cancer Research (2022)

Abstract Introduction: Head and neck cancer squamous cell carcinomas (HNSCC) are diverse and complex with inter-tumor and intra-tumor heterogeneity and discrepancies in therapy response regardless of the clinical stage. Tumors are thought to be heterogeneous at the single-cell level involving cancer stem cells. Therefore, cancer diagnosis and treatment are difficult because single cells might have intrinsic functional and genetic heterogeneity. Single cell transcriptome is used for mapping the genetic heterogeneity of a tumor. Currently, no model is available to provide a genotype to phenotype correlations for the heterogeneity, a crucial step for successful treat of a cancer. Here, our focus is to develop a single-cell clonal spheroid model system as a valuable tool for studying functional heterogeneity, including growth, proliferation, angiogenesis, metastasis, and genetic heterogeneity. Material and methods: HNSCC cell lines namely, UMSCC-22B, FaDu and A-253, and patients derived primary cells were cultured in 96-well ultra-low attachment to develop spheroids. Spheroids were cultured from 2, 4 and 128 cells per well with media, growth factors and supplements. Confocal microscopy was done using cocktail dyes including Hoechst, Calcein-AM and Ethidium bromide to check the functionality of spheroids. Results: We have established a method for the development of single-cell derived clonal spheroids. The frequency of spheroids formation from 2, 4 and 128 UMSCC-22B cells per well were higher than FaDu and A-253 cell lines. The growth measurement showed clones of single cell derived spheroids with hyperproliferation as well as with low proliferative activity. UMSCC-22B and A-253 hypoproliferative spheroids had significant higher migration capabilities compared to spheroids with hyperproliferative activity. Confocal microscopy of single-cell derived clonally propagated spheroids revealed a different zone viz proliferating, quiescent and necrotic zone in intact spheroids. This condition mimics in vivo conditions and suitable tool for drug penetration studies. Conclusion: Together, our results suggest that single cell-derived clonal spheroid from different wells would represent the genetic and functional heterogeneity of the cell population. Such a spheroid model can reveal heterogeneity inside a tumor formed by the proliferation of a single-cell and heterogeneity between tumors resulting from a different single cell and thus has great potential for drug discovery and tumor biology research. Citation Format: Jyoti Pandey, Ritis Shyanti, Sanjay V. Malhotra, Rupesh Chaturvedi, Rana P. Singh. Development of single cell spheroid as a tool to capture functional heterogeneity in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 10.
Enhancing the Trajectories of Cancer Health Disparities Research: Improving Clinical Applications of Diversity, Equity, Inclusion, and Accessibility
Authors: Rachel Martini, Endale Gebregzabher, Lisa Newman, Melissa B. Davis
Journal: Cancer Discovery (2022)

In order to accurately detect and prevent racial disparities, self-reported race (SRR) and ethnicity remain valuable tools; however, inaccurate capture of patient identity and broad aggregation of minoritized race groups present challenges for data interpretation. Also, although SRR is a proxy for shared social/cultural experience, it is not an accurate representation of shared endogenous factors. Biological investigations into cancer disparities, particularly those involving genetic features, should be framed in the context of genetic background or ancestry, as these are heritable aspects of population health. In reality, both genetics and environment work in concert to influence cancer risk and clinical outcomes. The best opportunity to define actionable means for reducing health disparities is in rigorous and comprehensive generation of rich data sets that characterize environmental, biological, and genetic components of disparate disease burden. To translate this pivotal disparities research into clinical tools and improved policies, we describe a diversity, equity, inclusion, and accessibility (DEIA) framework, which will increase participation from diverse backgrounds, reexamine previous research with a rigorous evaluation of appropriate SRR groupings, and engage community leaders to ensure that future research addresses the needs of communities at increased risk. On this path forward, we may finally end cancer disparities.
Gene fusion as an important mechanism to generate new genes in the genus Oryza
Authors: Yanli Zhou, Chengjun Zhang, Li Zhang, Qiannan Ye, Ningyawen Liu, Muhua Wang, Guangqiang Long, Wei Fan, Manyuan Long, Rod A. Wing
Journal: Genome biology (2022)

Abstract Background Events of gene fusion have been reported in several organisms. However, the general role of gene fusion as part of new gene origination remains unknown. Results We conduct genome-wide interrogations of four Oryza genomes by designing and implementing novel pipelines to detect fusion genes. Based on the phylogeny of ten plant species, we detect 310 fusion genes across four Oryza species. The estimated rate of origination of fusion genes in the Oryza genus is as high as 63 fusion genes per species per million years, which is fixed at 16 fusion genes per species per million years and much higher than that in flies. By RNA sequencing analysis, we find more than 44% of the fusion genes are expressed and 90% of gene pairs show strong signals of purifying selection. Further analysis of CRISPR/Cas9 knockout lines indicates that newly formed fusion genes regulate phenotype traits including seed germination, shoot length and root length, suggesting the functional significance of these genes. Conclusions We detect new fusion genes that may drive phenotype evolution in Oryza. This study provides novel insights into the genome evolution of Oryza.
Risk of Dementia After Smoking Cessation in Patients With Newly Diagnosed Atrial Fibrillation
Authors: Hui-Jin Lee, So-Ryoung Lee, Eue-Keun Choi, Sang-Hyun Park, Jae-Wook Chung, Jung-Min Choi, Min-Ju Han, Jin-Hyung Jung, Kyung-Do Han, Seil Oh, Gregory Y. H. Lip
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Incident atrial fibrillation (AF) is associated with an increased risk of dementia. However, data on the association between smoking cessation after AF diagnosis and dementia risk are limited. <h3>Objective</h3> To evaluate the association between changes in smoking status after AF diagnosis and dementia risk. <h3>Design, Setting, and Participants</h3> This nationwide cohort study with 126 252 patients used data from the Korean National Health Insurance Service database, including patients who had a national health checkup examination within 2 years before and after AF diagnosis between January 1, 2010, and December 31, 2016. Based on their smoking status, participants were classified as never smokers, ex-smokers, quit smokers, and current smokers. Ex-smokers were defined as those who had quit smoking before the first examination and remained quit until the second examination. Patients who were current smokers at the first health examination but had quit smoking before the second examination were classed as quit smokers. The index date was the second health examination. Patients were followed up until dementia, death, or the study period ended (December 31, 2017), whichever occurred first. Data were analyzed from January 13, 2020, to March 29, 2022. <h3>Exposures</h3> Smoking cessation after newly diagnosed AF. <h3>Main Outcomes and Measures</h3> Dementia, including Alzheimer disease and vascular dementia, was the primary outcome. Cox proportional hazards regression model was used to estimate hazard ratios. <h3>Results</h3> A total of 126 252 patients (mean [SD] age, 62.6 [12.0] years; 61.9% men) were included in the analysis. The mean (SD) CHA<sub>2</sub>DS<sub>2</sub>-VASc score, which measures the risk of ischemic stroke, was 2.7 (1.7). Smoking status of the total study population was as follows: 65 579 never smokers (51.9%), 34 670 ex-smokers (27.5%), 8919 quit smokers (7.1%), and 17 084 current smokers (13.5%). During a median of 3 years of follow-up, dementia occurred in 5925 patients (1.11 per 1000 person-years). After multivariable adjustment, the risk of quit smokers was significantly lower than that of current smokers (hazard ratio, 0.83 [95% CI, 0.72-0.95]). <h3>Conclusions and Relevance</h3> The findings of this cohort study suggest that all types of smoking were associated with a significantly higher risk of dementia in patients with new-onset AF. Smoking cessation after AF diagnosis was associated with a lower risk of dementia than among current smokers. These findings may support promoting smoking cessation to reduce dementia risk in patients with new-onset AF.
Abstract 2416: Ras-mediated activation of mTORC2 drives breast cancer cell migration and invasion
Authors: Mollie E. Wiegand, Shannon E. Collins, Isabella N. Brown, Alyssa N. Werner, Isabelle M. Mundo, Ghassan Mouneimne, Pascale G. Charest
Journal: Cancer Research (2022)

Abstract We previously identified the mechanistic Target of Rapamycin Complex 2 (mTORC2) as an effector of Ras for the control of directed cell migration in Dictyostelium. Recently, this relationship was found to be conserved in mammalian cells, and mTORC2 was shown to be an effector of oncogenic Ras. Deregulated mTORC2 signaling in cancer is mostly associated with increased survival and metabolic reprogramming, but mTORC2 has also been linked to cancer cell migration, particularly in breast cancer. Interestingly, although Ras is rarely mutated in breast cancer, it is often upregulated due to amplification and overexpression of growth factor receptors. Here, we investigated the role of Ras in promoting the migration and invasion of breast cancer cells through mTORC2. We observed that Ras and mTORC2 promote the migration of breast cancer cells, independently of the breast cancer molecular subtype. Using breast epithelial MCF10A cells transformed with HER2 or mutant Ras, we found that Ras promotes mTORC2 activation, and mTORC2-dependent migration and invasion. We further observed that while mutant Ras-transformed MCF10A cells display uncontrolled cell proliferation and an invasive phenotype, silencing of the mTORC2-dependent component Rictor mostly leads to loss of invasiveness. Together, our findings suggest that, whereas Ras activation of mTORC2 is likely to play a minor role in breast tumor formation, the Ras-mTORC2 pathway plays a key and general role in promoting the migration and invasion of breast cancer cells. Citation Format: Mollie E. Wiegand, Shannon E. Collins, Isabella N. Brown, Alyssa N. Werner, Isabelle M. Mundo, Ghassan Mouneimne, Pascale G. Charest. Ras-mediated activation of mTORC2 drives breast cancer cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2416.